Cancer initiating cells (CICs) exhibit distinct markers and are highly tumorigenic. Several research groups have successfully isolated colorectal cancer initiating cells (CCICs) based on distinct cell-surface markers. Conventional therapies, including chemotherapies and radiotherapies, target the bulk population of rapidly proliferating colorectal cancer cells. Although a large proportion of tumor mass is eradicated, therapy-resistant CCICs remain and can differentiate into non-CCIC cancer cells. Repopulation of the tumor over time by the progenies of CCICs ultimately results in a more aggressive phenotype than the initial pretreated malignancy. With 56,500 fatalities per year, colorectal cancer is second only to lung cancer as a cause of cancer deaths in the USA. Each year, 150,000 to 160,000 new cases are diagnosed of which 10 to 20% already have liver metastases. About 70% of all colorectal cancer patients eventually develop liver metastases. Hepatic resection is currently the only form of treatment that offers long-term survival, with 5-year survival rates ranging from 25% to 39%. Using the current selection criteria for hepatectomy, only 10% to 20% of all patients are candidates for curative operation. The prognosis for the remaining patients is grim with palliative chemotherapy and symptomatic treatments being the only available options. There are no reliable treatment modalities for controlling cancer recurrence after chemotherapy. Our laboratory has found that paired immunoglobulin-like receptor B (PIRB) and its human ortholog leukocyte Ig-like receptor B (LILRB) play an important role in controlling the stemness of colon cancer initiating cells (CIC) and induction of epithelial-mesenchymal transition (EMT). Recently, Angiopoietin-like proteins (Angptls) have been identified as a nature high affinity ligand for PIRB/LILRBs. We found that PIRB activation, through its high affinity ligands, angiopoietin like protein 2 (Angptl-2, mouse) and Angptl-2 and -5 (human), promoted acquisition of an M2 (alternative) macrophage functional phenotype by myeloid-derived suppressor cell, induced CIC phenotypes of colon tumor cells, and enhanced metastases. We hypothesize that PIRB/LILRB signaling through ligation of Angptl can induce the phenotype of colon cancer initiating cell and EMT, thereby facilitating the development of chemotherapy resistance. Thus, blockade of PIRB/LILRB signaling may prevent colon cancer relapse after chemotherapy. Three specific aims are proposed. In Aim 1, we will determine the effect of Angptls on proliferation and maintenance of stemness of colon tumor cell lines, based on the expression of PIRB/LILRB. In Aim 2, we will assess the effect of Angptl expression induced by chemotherapy on CIC and EMT phenotypes. In Aim 3, we will evaluate the effect of blocking PIRB/LILRB signaling, alone or in conjunction with chemothrapy therapy, on colon cancer initiating cells and myeloid differentiation. Our study will identify the molecular determinants of Angptl receptor-mediated signaling in control of CCIC and EMT phenotypes, and provide new information for devising a novel therapeutic modality for refractory colorectal cancer.